The basic composition of mammalian heterochromatin


Project Summary

Deregulation of most heterochromatin core components has been linked to complex human disorders that display a strong epigenetic contribution. We will reconstruct heterochromatin by insertion of repeat elements into inert genomic regions. In addition, the transcriptional response of repeat-rich heterochromatin by epigenetic inhibition of chromatin-modifying enzymes will be investigated. Together, these approaches will provide new insights into the genome-wide profile and adaptability of mammalian heterochromatin, as it will be relevant for normal and perturbed development.

Selected project-relevant publications

  • Djeghloul D., Dimond A., Cheriyamkunnel S., Kramer H., Patel B., Brown K., Montoya A., Whilding C., Wang Y.F., Futschik M.E., Veland N., Montavon T., Jenuwein T., Merkenschlager M. and Fisher A.G. (2023) Loss of H3K9 trimethylation alters chromosome compaction and transcription factor retention during mitosis. Nat Struct Mol Biol 30, 489-501.
  • Montavon T., Shukeir N., Erikson G., Engist B., Onishi-Seebacher M., Ryan D., Musa Y., Mittler G., Meyer A.G., Genoud C. and Jenuwein T. (2021) Complete loss of H3K9 methylation dissolves mouse heterochromatin organization. Nat Commun 12, 4359.
  • Duda K.J., Ching R.W., Jerabek L., Shukeir N., Erikson G., Engist B., Onishi-Seebacher M., Perrera V., Richter F., Mittler G., Fritz K., Helm M., Knuckles P., Bühler M. and Jenuwein T. (2021) m6A RNA methylation of major satellite repeat transcripts facilitates chromatin association and RNA:DNA hybrid formation in mouse heterochromatin. Nucleic Acids Res 49, 5568-5587.
  • Walther M., Schrahn S., Krauss V., Lein S., Kessler J., Jenuwein T. and Reuter G. (2020) Heterochromatin formation in Drosophila requires genome-wide histone deacetylation in cleavage chromatin before mid-blastula transition in early embryogenesis. Chromosoma 129, 83-98.
  • Burton A., Brochard V., Galan C., Ruiz-Morales E.R., Rovira Q., Rodriguez-Terrones D., Kruse K., Le Gras S., Udayakumar V.S., Chin H.G., Eid A., Liu X., Wang C., Gao S., Pradhan S., Vaquerizas J.M., Beaujean N., Jenuwein T. and Torres-Padilla M.E. (2020) Heterochromatin establishment during early mammalian development is regulated by pericentromeric RNA and characterized by non-repressive H3K9me3. Nat Cell Biol 22, 767-778.
  • Healton S.E., Pinto H.D., Mishra L.N., Hamilton G.A., Wheat J.C., Swist-Rosowska K., Shukeir N., Dou Y., Steidl U., Jenuwein T., Gamble M.J. and Skoultchi A.I. (2020) H1 linker histones silence repetitive elements by promoting both histone H3K9 methylation and chromatin compaction. Proc Natl Acad Sci U S A 117, 14251-14258.
  • Nicetto D., Donahue G., Jain T., Peng T., Sidoli S., Sheng L., Montavon T., Becker J.S., Grindheim J.M., Blahnik K., Garcia B.A., Tan K., Bonasio R., Jenuwein T. and Zaret K.S. (2019) H3K9me3-heterochromatin loss at protein-coding genes enables developmental lineage specification. Science 363, 294-297.
  • Velazquez Camacho O., Galan C., Swist-Rosowska K., Ching R., Gamalinda M., Karabiber F., De La Rosa-Velazquez I., Engist B., Koschorz B., Shukeir N., Onishi-Seebacher M., Van De Nobelen S. and Jenuwein T. (2017) Major satellite repeat RNA stabilize heterochromatin retention of Suv39h enzymes by RNA-nucleosome association and RNA:DNA hybrid formation. Elife 6, doi: 10.7554/eLife.25293.
  • Allis C.D. and Jenuwein T. (2016) The molecular hallmarks of epigenetic control. Nat Rev Genet 17, 487-500.
  • Bulut-Karslioglu A., De La Rosa-Velazquez I.A., Ramirez F., Barenboim M., Onishi-Seebacher M., Arand J., Galan C., Winter G.E., Engist B., Gerle B., O’sullivan R.J., Martens J.H., Walter J., Manke T., Lachner M. and Jenuwein T. (2014) Suv39h-dependent H3K9me3 marks intact retrotransposons and silences LINE elements in mouse embryonic stem cells. Mol Cell 55, 277-290.
  • Bulut-Karslioglu A., Perrera V., Scaranaro M., De La Rosa-Velazquez I.A., Van De Nobelen S., Shukeir N., Popow J., Gerle B., Opravil S., Pagani M., Meidhof S., Brabletz T., Manke T., Lachner M. and Jenuwein T. (2012) A transcription factor-based mechanism for mouse heterochromatin formation. Nat Struct Mol Biol 19, 1023-1030.
  • Pinheiro I., Margueron R., Shukeir N., Eisold M., Fritzsch C., Richter F.M., Mittler G., Genoud C., Goyama S., Kurokawa M., Son J., Reinberg D., Lachner M. and Jenuwein T. (2012) Prdm3 and Prdm16 are H3K9me1 methyltransferases required for mammalian heterochromatin integrity. Cell 150, 948-960.
  • Rea S., Eisenhaber F., O’carroll D., Strahl B.D., Sun Z.W., Schmid M., Opravil S., Mechtler K., Ponting C.P., Allis C.D. and Jenuwein T. (2000) Regulation of chromatin structure by site-specific histone H3 methyltransferases. Nature 406, 593-599.